Roche, perhaps, more than any other pharmaceutical company, is banking heavily on the combination of diagnostics and drug development to drive pharmaceutical innovation. In reporting its 2010 results in February 2011, Roche reported that it had 12 new molecular entities in late-stage development, of which six were potential personalized healthcare medicines with planned companion diagnostic tests, which included Zelboraf (vemurafenib) and its companion diagnostic for BRAF mutation-positive metastatic melanoma. FDA approved Zelboraf for treating BRAF V600E mutation-positive, inoperable, or metastatic melanoma and the cobas 4800 BRAF V600 Mutation Test, a diagnostic test developed by Roche, in August 2011.

Earlier this month, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended that Zelboraf be granted full marketing authorization as a monotherapy for treating adult patients with BRAF V600 mutation-positive unresectable or metastatic melanom. The corresponding European Commission decision on the marketing authorization of Zelboraf is expected in February 2012. Marketing authorization submissions for Zelboraf also are under review by health authorities in Australia, New Zealand, Brazil, India, Mexico, Canada, and other countries worldwide.

Roche also is using its diagnostic strategy to support new indications for existing drugs. Last month, Roche reported that the cobas EGFR Mutation Test was CE-marked, an indicator of a product’s conformity with EU requirements, and is now commercially availabile in Europe and other countries that recognize the CE mark. The cobas EGFR Mutation Test is a companion diagnostic to identify patients with non-small-cell lung cancer (NSCLC) who harbor mutations in the EGFR (epidermal growth factor receptor) gene and who may benefit from treatment with anti-EGFR tyrosine kinase inhibitors, such as Roche’ Tarceva (erlotinib). Tarceva, an oral EGFR inhibitor, was first approved in September 2004 to treat locally advanced or metastatic NSCLC after failure of at least one other chemotherapy treatment. It later was approved by the European Commission in September 2011 as a first-line monotherapy in people with locally advanced or metastatic NSCLC with EGFR-activating mutations.

Other companies also are reporting success with certain personalized medicines. In August 2011, FDA approved Pfizer’s Xalkori (crizotinib) for treating locally advanced or metastatic NSCLC that expresses the abnormal anaplastic lymphoma kinase (ALK) as detected by an FDA-approved test. The agency approved the drug along with a diagnostic test for the ALK gene abnormality, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit. Up to 7% of those patients with NSCLC, typically patients without a history of smoking, have the gene abnormality.

Although personalized medicines will likely hold only a small part of the overall pharmaceutical market by value and volume in the near term, these successes portend of a changing paradigm in drug development.

Under a user-fee program, industry agrees to pay fees to help fund a portion of the FDA’s drug-review activities while the FDA agrees to overall performance goals, such as reviewing a certain percentage of applications within a particular timeframe. The proposed user-fee programs for generic drugs and biosimilars are modeled on the PDUFA program. PDUFA was created by Congress in 1992 and must be reauthorized every five years. The current program, known as PDUFA IV, will expire on Sept. 30, 2012, unless reauthorized by Congress. FDA’s recommendations for PDUFA V were developed in consultation with drug-industry representatives and with patient and consumer advocates, according to an FDA press release.

The proposed new generic-drug user-fee program would provide the FDA with funding at a time when generic-drug applications are on the rise. FDA receives 800 to 900 new generic-drug-related applications annually, according to the agency. In exchange for fees on facilities and product applications, the proposal includes performance metrics, such as review timeframes and a commitment to achieve parity between surveillance inspections of foreign and domestic establishments by fiscal year 2017. FDA expects that the proposal would effectively eliminate the review backlog and significantly reduce review times.

The Generic Pharmaceutical Association (GPhA) issued its support for a proposed Generic Drug User Fee Act (GDUFA) and FDA’s recommendations for a generic-drug user-fee program. “This is an important landmark that could not have been achieved without the extraordinary efforts of the FDA, my colleagues in the generic industry, and all other stakeholders,” said Ralph G. Neas, President and CEO of GPhA, in a Jan. 13, 2012, GPhA statement. “We now look forward to working with members of Congress in the weeks and months ahead to ensure that the final program is one that expedites access to low-cost, high-quality generic drugs for Americans and further safeguards the quality and accessibility of our nation’s drug supply.”

GDUFA calls for the generic-drug industry to pay $299 million annually in user fees for the next five years, beginning Oct. 1, 2012. This funding is supplemental to what Congress appropriates to FDA each year and will enable  FDA’s Office of Generic Drugs to hire the scientific resources needed to provide timely approval of generic medicines, according to GPhA. The new fees also will boost spending for generic-drug manufacturer facility inspections, which are required before new generic drugs can be approved.

The proposed Biosimilar and Interchangeable Products User Fee program is intended for products approved under a new abbreviated approval pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological product. The Affordable Care Act of 2010 contains a subtitle called the Biologics Price Competition and Innovation Act of 2009, which established this pathway. The recommended user-fee program for biosimilars includes fees for products in development to generate revenue in the near term and to provide FDA with the resources needed to support development-phase meetings with sponsors of biosimilar biological product candidates.

The Pharmaceutical Research and Manufacturers of America (PhRMA) supports the premise of a biosimilar user-free program.” We endorse a clear, science-based, separately funded regulatory program for biosimilars that is supported by a mix of appropriations dollars and user fees,” said a PhRMA Vice-President Sascha Haverfield-Gross in a Dec. 6, 2011, statement.

The Biotechnology Industry Organization (BIO) did not comment on the proposed generic-drug and biosimilar user-fee programs, but offered its support for the reauthorization of PDUFA. “BIO strongly supports the PDUFA V recommendations as they will enhance the drug-development and review process through increased transparency and scientific dialogue, advance regulatory science, and strengthen postmarket surveillance,” said BIO president and CEO Jim Greenwood, in a Jan. 13, 2012, statement. “Most importantly, PDUFA V will provide patients and doctors with earlier access to innovative new therapies.”

Congress will take up the issue of user fees in a series of Congressional hearings, scheduled for next month. The House Energy and Commerce Health Subcommittee will hold hearings on Feb. 1, 2012, on PDUFA reauthorization and on Feb. 7, 2012, on the proposed generic-drug user fee and biosimilar user-fee programs. Senators Tom Harkin (D-IA) and Mike Enzi (R-WY), the chairman and ranking member of the Senate Committee on Health, Education, Labor and Pensions (HELP), offered their support for the PDUFA reauthorization and the proposed generic-drug and biosimilar user fee programs. “These user fee agreements are crucial to ensuring that medications become available to the American public quickly and safely,” said the senators in joint Jan. 13, 2012, statement. “We applaud the FDA and the industries for the dedication and hard work it took to finalize these agreements.” During the past several months, the HELP Committee has convened a series of hearings to explore issues related to the user-fee legislation.

With strong fiscal constraints, the user-fee programs, both the PDUFA reauthorization and user-fee programs for generic drugs and biosimilars seem likely. The key item in the coming months is to see if Congress will be able to move forward with the initiatives per FDA’s recommendations.

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Beginning this month, we are featuring monthly reader polls to gain your feedback on key advances in the pharmaceutical sciences and manufacturing. As the scientists and technical experts on the front lines, your input is a crucial component in understanding what the industry has achieved and where it will go in the future. We encourage you to provide your feedback in our first poll, which is examining advances in oral drug delivery and oral product forms. We will share the results with you at PharmTech.com, and along with further analysis, our July issue will take a retrospective and prospective look at drug substance and finished drug-product manufacturing, formulation development and drug delivery, outsourcing, and analytical testing.

We are interested in your feedback as well. In addition to our reader polls, we invite you to provide your input on what you think have been major achievements in drug substance and finished drug-product manufacturing, formulation development and drug delivery, outsourcing, and analytical testing. Lend your expertise and offer your input in the comment section to this blog or email your input to Patricia Van Arnum, executive editor, pvanarnum@advanstar.com. We look forward to hearing from you.

Citing interviews with stakeholders, GAO recommended creating an information clearinghouse, through which companies could share information anonymously on adulterated ingredients with FDA and other companies. A clearinghouse could help FDA disseminate information about adulterated products quickly and enable the agency and industry to respond to adulteration rapidly. If the clearinghouse were managed by a neutral third party, it could ensure that the information did not identify specific companies.

This strategy could help allay industry’s concerns about sharing information when an adulterated ingredient has not entered into commerce. Companies are afraid that they may be sued if they reported that a supplier intentionally adulterated a product and the accusation is later found to be baseless. A wrongful accusation “can have serious consequences, such as compromising the integrity of the company’s brands and products if certain information became public,” according to the report.

Because potential adulterants often are unknown or unidentified, it can be hard for FDA to detect them. “For example, during the heparin incident, the available test methods for heparin were not able to detect the contaminant oversulfated chondroitin sulfate,” said the report. “Industry may be the best source of tests to detect adulteration because companies develop such tests to monitor the products they receive from their suppliers; however, industry officials indicated that they are often reluctant to share such information because it is proprietary.”

By eliminating details that could identify specific pharmaceutical companies, an information clearinghouse could allay industry’s concerns, help FDA dedicate its resources efficiently in the event of potential adulteration, and protect citizens from ingesting harmful drugs. It sounds like a win for all involved. GAO has done us a service in writing this report, and I hope FDA takes its recommendations seriously.

The rationale for such an approach is clear. One needs to only look  down the rows of the more than 1800 exhibitors at CPhI to see the requisite  for contract-service providers and suppliers to achieve competitive advantage through product and service differentiation. For pharmaceutical companies, among the more than 25,000 attendees at CPhI, the decision of with whom to partner is crucial for successfully implementing their drug-development and manufacturing strategies.

The strategic partnership model was discussed at a conference session at CPhI. Moderated by Jim Miller, president of PharmSource Information Services and contributing editor to Pharmaceutical Technology, the panel featured presentations from Sanjit Singh Lamba, managing director of the  Knowledge Center for Eisai, Massimiliano Brescia, global pharmaceutical operations at Abbott, and  Philip Pratten, vice-president of business development, contract pharma services with Alkermes.  The panelists discussed the drivers behind the adoption of strategic partnerships and best practices in optimizing such relationships.

For pharmaceutical companies, they face ongoing pressure to reduce costs while maintaining quality and security of supply, are seeking to   reduce their supplier base to more efficiently manage their drug-development activities and manufacturing network on a global basis, and want to gain continuous improvement and innovation in technology, processes, and  project management. For contract service providers, such strategic partnerships are a way to meet the expanding and diverse needs of pharmaceutical customers  by building long-term and stable relationships. The panelists shared perspectives on performance metrics, communication approaches, and best practices in technology transfer in meeting the evolving needs of pharmaceutical companies.

So what is the take-away? Effective relationship builing, project-management competency, continuous-improvement strategies, and supplier innovation are evermore important elements of the toolboxes of contract-service providers.

The answer to that question as it was discussed reflected many of the larger and well-chronicled trends affecting the pharmaceutical industry, such as generic-drug incursion, declining R&D productivity, and the ongoing need for cost reduction in development and manufacturing. At one level, these pressures make outsourcing an attractive alternative to internal development and manufacturing as a means to reduce fixed cost structures and achieve greater flexibility, which is a plus for CROs and CMOs. On the downside, however, CROs and CMOs face greater competition as pharmaceutical companies, particularly large pharmaceutical companies, seek to reduce their supplier base and partner with strategic, if not preferred, providers as the choices for these potential CROs and CMOs broaden globally.

So how do CROs and CMOs make the cut or stay in the game and achieve a competitive advantage? Some suggestions offered by pharmaceutical companies were integrated service offerings, higher levels of project management, specialized technical offerings, and other approaches that meet the evolving needs of pharmaceutical companies in realizing their goals for greater flexibility while maintaining reliability and quality of supply. The choices for CROs and CMOs relate to how to adapt their business models either through increased service offerings, partnering with other contract service organizations to achieve a fuller slate of capabilities, and finding opportunity in the globalization of the pharmaceutical contract service industry. Not an easy task, but one in which has become a basic requirement for participation in the market for pharmaceutical chemical outsourcing.

Alleviating API inspection fatigue

The first pilot involved the EMA, the national regulatory agencies of several EU member states, the FDA and Australia’s Therapeutic Goods Administration (TGA), and concerned joint GMP inspections of API manufacturers. Such inspections have been a hot topic in the industry for some time because they offer the two-fold benefit of increasing the total number of sites inspected and reducing duplicate inspections for manufacturers. According to the final report on the programme, participants shared their surveillance lists and identified 97 sites common to all three regions, resulting in the exchange of nearly 100 inspection reports and 9 joint inspections. The pilot ran from December 2008 until December 2010 and, according to the report, collaboration in this area will continue and expand—initially to other European authorities.

“The increased cooperation established as a result of the pilot programme increased information sharing between the regulators concerned and facilitates work sharing,” explained the final report on the programme. “It also promoted more efficient use of international inspectional resources combined with wider global inspectional coverage to the benefit of public health and patients worldwide.”

The FDA also touted the success of the initiative in a press statement; for instance, the FDA prohibited imports into the US of a firm’s products based on the negative findings from a European inspection. “The information-sharing and collaborative inspections were important milestones in establishing a sense of mutual trust and common purpose among the drug regulatory agencies involved,” said the FDA in its statement.

Improving GCP

The second pilot involved the EMA and the FDA, and was launched in September 2009 with the objective of sharing inspections information and GCP-related documents, and conducting joint inspections. As with the above pilot, the programme has been very productive. The agencies exchanged more than 250 documents relating to 54 different medicines and organised 13 joint inspections.

The final report said: “A considerable amount of information has been exchanged, and this communication has facilitated improvements in the agencies’ inspection coverage and decision-making processes. The thirteen collaborative inspections conducted under this initiative have contributed greatly to each agency’s understanding of the other’s inspection procedures; they have also led to the identification of potential improvements to these procedures.”

The agencies have said that the initiative will continue and that they will incorporate the lessons learned during the pilot. In a statement, the EMA said that the pilot “demonstrates how the agencies can work together to improve the protection of participants in clinical trials and better ensure the integrity of data submitted as the basis for drug approvals.”

Working out the bumps

But it’s not all going to be smooth sailing from now on. The collaboration is, of course, still in its early days and there are some bugbears that need to be worked out. For example, during the API inspection pilot, particularly in 2009, the report notes that a number of duplicate inspections occurred due to issues related to the ‘Master List’ of API sites, such as out-of-date information. Tools that enable the real-time sharing of data, however, may be able to assist in this area. Another challenge identified was the organisation of joint inspections; several inspections were cancelled because of the absence of effective advance planning and logistical issues. As a recommendation, the reports said that the planning of joint inspections should commence as early as possible.

Overall, the reactions from the agencies involved has been positive, with the FDA describing the pilots in a press statement as “important stepping stones toward further global regulatory collaboration”.

Moving forward, however, caution has been expressed about opening the project wider at this early point because of the added complexity. For now, the collaboration will continue in the existing format and will be extended to all the member states of the European Economic Area. As the bumps in the road are gradually smoothed, however, perhaps there will be input from additional parties. The report said: “Nevertheless, it is recognised that extending the programme to more comparable regulatory authorities and possibly the World Health Organisation would certainly need to be considered as a long-term goal, as an efficient worldwide programme of inspections of APIs would be a notable benefit for public health globally.”

The final reports can be downloaded from either the EMA or FDA websites. If you’re looking for some extra reading to get you through Friday, then you can also have a look at these related PharmTech articles:

FDA, EMA, say future inspections likely

Joint API inspections on the rise

Some key drug approvals thus far in 2011 include AstraZeneca’s Brilinta (ticagrelor), a cardiovascular drug, which is being positioned as a potential blockbuster to complete against the platelet inhibitor Plavix (clopidogrel) by Bristol-Myers Squibb and Sanofi, according to an Aug.1, 2011, press release by Burrill & Company, a life-sciences financial-services firm. Plavix was the second highest selling drug in 2010 on a global basis, trailing only Pfizer’s Lipitor (atorvastatin), which was the top-selling drug. In 2010, Plavix posted global sales of $8.8 billion, according to IMS Health.

Other key approvals thus far in 2011 were: Incivek (telaprevir), a hepatitis C drug by Vertex Pharmaceuticals; Yervoy (ipilimumab), a melanoma drug by Bristol-Myers Squibb; and Benlysta (belimumab), a lupus drug by Human Genome Sciences, noted the Burrill & Company analysis. More than a dozen other drug candidates are scheduled for FDA review by the end of the year, according to the Burrill analysis.

As noted by Burrill & Company, seven months of data in terms of approvals does not in of itself make a change  in terms of improved R&D drug productivity, but at least it is a positive sign. During the past five years (2006–2010), FDA has approved on average 22 new drugs per year (21 in 2010, 26 in 2009, 24 in 2008, 18 in 2007, and 22 in 2006), according to FDA information. The recent 10-year high was in 2004, when FDA approved 36 new drugs.

It is not likely that in 2011 or in the near term, the industry will reach the level of productivity achieved in 2004, but at least thus far in 2011, there is good news on the drug-approval front.

Understanding critical quality attributes will help Pfizer develop robust design spaces and, ultimately, achieve real-time release, said Gerry Migliaccio, senior vice-president of network performance for Pfizer Global Supply, according to In-Pharma Technologist. Migliaccio made his remarks at a meeting of FDA’s Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. Using QbD as a basis, and process analytical technology to establish manufacturing controls, Pfizer believes it will be able to reduce quality-control costs, achieve real-time release, and quickly get a return on its investment.

But not all companies are rushing to adopt QbD. Manufacturers of small-molecule generic drugs fear that spending the extra initial time and effort to adopt QbD could prevent them from being the first to file an application for their products. “If you’re not first to file, you may as well be last,” said Yatindra Joshi, vice-president of generics R&D for Teva, at the same FDA meeting. Consequently, some generic-drug manufacturers aren’t willing to gamble that the benefits of QbD will outweigh the profits lost by not being first to file.

If Pfizer and other heavyweights adopt QbD, it could boost patients’ confidence in the safety and efficacy of marketed drugs. But patients would benefit even more if generic-drug manufacturers felt freer to pursue this initiative. By making some elements of QbD mandatory in filings, FDA could “level the playing field,” said Joshi. This idea seems like one plausible solution that could be of advantage to the industry and consumers alike.

For FDA’s evaluation of the QbD program so far, please watch for Pharmaceutical Technology’s September issue, in which CDER’s Helen Winkle and Moheb Nasr analyze the initiative’s present and future.

According to the Premier healthcare alliance, a performance-improvement alliance of 2500 US hospitals and 75,000 healthcare sites, drug shortages cost US healthcare providers at least $200 million annually. “These drug shortages increase the risk to patients due to the introduction and use of unfamiliar drugs to work around the shortages,” states a Premier press release from March 2011.

For many years, FDA has run a Drug Shortage Program aimed at addressing “potential or actual shortages of drugs that have a significant impact on public health.” Current shortages are kept up to date on the site. Among the most recent shortages listed are Genentech’s Tamiflu for Oral Suspension and several injections. The information provided on the site is provided voluntarily by manufacturers (they are not required to do so). The agency encourages healthcare professionals and patients as well to notify it about any other known shortages at drugshortages@fda.hhs.gov.

In 2010, there were 178 drug shortages reported to FDA, 132 of which involved sterile injectable drugs, according the agency’s frequently asked questions (FAQ) website for the program. This year, to date, there has been “an increasing number of shortages, especially those involving older sterile injectable drugs,” says the site. These shortages have involved cancer drugs, anesthetics used for patients undergoing surgery, as well as drugs needed for emergency medicine, and electrolytes needed for patients on IV feeding.

For the most part, these shortages have been caused by quality and manufacturing issues, says the FDA FAQ website. Other causes are tied to delays with getting raw materials or components from suppliers, or discontinuations of certain products (which FDA does not have the authority to stop). “With fewer firms making older sterile injectable drugs, there are a limited number of production lines that can make these drugs,” says the FDA website.

The agency works with companies to address quality and manufacturing problems and to help ramp up production, where appropriate, by expediting the approval of new production lines or raw-material sources. The agency also, in some cases, approaches overseas companies that may be able to fill any gaps in product shortages.

Earlier this year, two US Senators introduced the Preserving Access to Life-Saving Medications Act (S. 296) to amend the Federal Food, Drug, and Cosmetic Act to provide FDA with improved capacity to prevent drug shortages, including the way the agency prioritizes reinspections. According to the draft legislation, the Secretary of the US Department of Health and Human Services would have to submit an annual report to Congress about actions taken to address drug shortages all through the supply chain. To date, the bill is still in committee. A companion House bill, H.R. 2245, is also in committee.

Many groups have been lobbying Congress on this topic. For example, drug shortages are a key issue for cancer patients. The Association of Community Cancer Centers hosted a Capitol Hill briefing on July 13, 2011, to present data from a new survey showing that 94% of reporting facilities in 2010-2011 experienced an oncology drug shortage. Eighty-four percent of those facilities said they had to “temporarily modify or suspend a chemotherapy regimen for their patients because they were unable to obtain a specific drug,” according to a blog on the ACC site.

I find it surprising that manufacturers are not required to alert FDA to shortages, whether pending or imminent, considering the impact a shortage can have on patient care and the industry in general. Even the FDA itself says that “significant public health consequences that can result from drug shortages,” on its FAQ site. Manufacturers are also not required to report the reasons for shortages or the shortages’ expected duration. They are required, however, to let FDA know six months in advance about any discontinuations of sole-source products.

FDA is holding a public workshop on this topic on Sept. 26, 2011, in Silver Spring, Maryland. The focus will be on how FDA’s Center for Drug Evaluation and Research is addressing the issue, the causes and impacts of shortages, and potential strategies for preventing them in the future. Let’s hope the workshop helps move forward the pending legislation in Congress so that regulators, industry, and healthcare providers can better prepare for and control the effects of drug shortages in the future.